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The story behind the discovery: The role of the “virgin” brain

Apprenticeship is foundational to scientific education. Graduate studies students and post-doctoral fellows work in established labs to learn the ropes of research from seasoned scientists. Through this model, it is expected that knowledge will be transferred from the more experienced to the less, allowing science to progress.

Occasionally, however, the inverse is true and the master can learn a thing or two from the novice.

“Students and fellows don’t get as much credit as they should, but their fresh thinking is very good for science,” said Virginia Brooks, PhD, Professor, Department of Physiology & Pharmacology. “While this happens in bits and pieces all the time, a particularly great example occurred in my lab about five years ago when a new graduate student kicked us out of a rut and pushed our thinking in an entirely new direction.”

The story has to do with one of the long-standing core interests of the Brooks lab – unraveling the mechanics of the baroreceptor reflex, a blood pressure control mechanism. Many conditions, as diverse as pregnancy, obesity and Alzheimer’s disease, are associated with an impaired baroreceptor reflex. This impairment can lead to instability in blood pressure levels, which can cause organ damage and other health-threatening effects.

“When Daisy Daubert began her thesis work, we were conducting a series of experiments to try to pinpoint specifically how pregnancy impairs the baroreflex,” recalled Dr. Brooks. “We were keen to identify the mechanisms, because hemorrhage accompanies every delivery, and the baroreflex is the major mechanism that helps to stabilize blood pressure during blood loss.”

Because pregnancy impairs the baroreflex, peripartum hemorrhage is a major cause of maternal death.

“As happens in many scientific explorations, the experiments were not panning out. Many hypotheses had been rejected,” said Dr. Brooks. In a moment of frustration, Dr. Brooks jokingly told Daisy, “I give up, you figure it out.”

Daisy accepted the challenge and buried herself in the scientific literature, considering all the relevant information from a “virgin” perspective. Her plan of attack was to look for any common elements among the full suite of diverse conditions in which an impaired baroreceptor reflex manifested.

Two days later, Daisy came back to the lab with an observation – insulin resistance, also known as decreased insulin sensitivity, was associated with all the conditions.

At the time, the observation led to what was an improbable set of hypotheses.

Insulin helps blood sugar (glucose) enter cells. Insulin resistance means that the body does not respond to the insulin, and blood sugar cannot get into cells. As a result, the body produces more and more insulin, blood sugar levels rise, dangerously affecting kidney function and raising the level of blood fats, such as triglycerides.

Was insulin resistance also a controlling factor in the baroreceptor reflex? If so, how?

The novelty of the hypotheses had to do with insulin in the brain. While not made there, insulin enters the brain by active transport across the relatively impervious capillary blood-brain barrier. Once in the brain, insulin binds to specific receptors in multiple but discrete brain sites to influence many bodily functions, from appetite suppression to memory.

Over the next several years, this line of investigation proved very fruitful. Daisy’s thesis work and subsequent experiments eventually confirmed that insulin plays a role in the mechanics of the baroreceptor reflex and suggested that the brain requires insulin for optimal baroreflex function. The work further identified where in the brain insulin initiates this action and what goes wrong in insulin resistant conditions like pregnancy and obesity, resulting in impaired baroreflex function.

The results of this research have now been widely published, including in a recent edition of the Journal of Physiology (Cassaglia et al.) The abstract from the paper states:

“Though the pancreatic hormone insulin is known to act in the brain to increase sympathetic nerve activity and baroreflex control of sympathetic nerve activity, its specific site of action had yet to be identified. We show that a region in the hypothalamus, the arcuate nucleus, is the site at which insulin’s effects are initiated. This new information may lead to a greater understanding of the role of insulin in the brain in adverse cardiovascular complications, like hypertension and heart attacks, which are associated with insulin-resistant states, such as obesity and diabetes.”

After defending her thesis in 2007, and engaging in a 2 year postdoctoral fellowhip, Daisy accepted a position as Assistant Professor of Biology at Ferris State University in Big Rapids, Mich.

The Brooks Lab continues to focus on the brain actions of insulin. Recent studies have demonstrated that the “insulin hypothesis” applies to another insulin resistant state, obesity. Now that the brain site of action of insulin has been identified, current and future work aims to understand the cellular-molecular mechanisms of insulin action in neurons and how insulin resistant states modify these actions. Currently, there are four students and fellows in the Brooks Lab. “I love having students in the lab. As we guide them on their journey to becoming an independent investigator, we can learn something along the way as well.”